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    Aster tataricus alleviates constipation by antagonizing the binding of acetylcholine to muscarinic receptor and inhibiting Ca influx. Wu Hao,Chen Yijun,Huang Beibei,Yu Yingting,Zhao Shujun,Liu Jie,Jia Zhixin,Xiao Hongbin Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie BACKGROUND:The dried root and rhizome of Aster tataricus (RA), is a traditional Chinese medicine has been used for more than 2000 years with the function of antitussive, expectorant and antiasthmatic. Ancient books and modern pharmacological researches demonstrated that RA may have the function of moistening intestines and relieving constipation, but there was a lack of systematic evidence. The aim of this study was to comprehensively evaluate the efficacy and possible mechanisms of ethanol extract of Aster tataricus (ATE) in treating constipation from in vivo to in vitro. METHODS:In vivo, the ATE was studied in loperamide-induced constipation of mice. In vitro, different concentrations of ATE was tested separately or cumulatively on spontaneous and agonists-induced contractions of isolated rat duodenum strips. RESULTS:In vivo, at doses of 0.16, 0.8 g/mL, ATE showed significantly promotion of the small intestinal charcoal transit, decrease of the amount of remnant fecal, and increase of the content of fecal water in colon. In addition, ATE could effectively relieve colonic pathological damage caused by loperamide as well. In vitro, with the cumulative concentration increase of ATE from 0.8 to 6.4 mg/mL, it could significantly decrease the contraction caused by KCl or Ach, and gradually restore to near base tension value.Meanwhile, it could also partially but significantly inhibit the contractions induced by Ach and CaCl on rat duodenum in a concentration related manner. CONCLUSIONS:Taking all these findings together, it could be speculated that ATE may attenuate constipation mainly through antagonizing the binding of acetylcholine to muscarinic receptor, inhibiting Ca influx and anti-inflammation. 10.1016/j.biopha.2020.111005
    Antioxidant activity and laxative effects of tannin-enriched extract of Ecklonia cava in loperamide-induced constipation of SD rats. Kim Ji Eun,Choi Yun Ju,Lee Su Jin,Gong Jeong Eun,Lee Young Ju,Sung Ji Eun,Jung Young Suk,Lee Hee Seob,Hong Jin Tae,Hwang Dae Youn PloS one To investigate the role of tannin-enriched extracts of Ecklonia cava (TEE) on the regulation of oxidative balance and laxative activity in chronic constipation, we investigated alterations after exposure to TEE, on constipation phenotypes, muscarinic cholinergic regulation, and oxidative stress responses in the transverse colons of SD rats with loperamide (Lop)-induced constipation. This extract contains high levels of total condensed tannin content (326.5 mg/g), and exhibited high inhibitory activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) radicals. TEE treatment induced significant improvements in reactive oxygen species (ROS) production, superoxide dismutase (SOD) expression and nuclear factor erythroid 2-related factor 2 (Nrf2) phosphorylation in primary smooth muscles of rat intestine cells (pRISMCs) and transverse colon of constipation model. Also, Lop+TEE treated groups showed alleviated outcomes for the following: most stool parameters, gastrointestinal transit, and intestine length were remarkably recovered; a similar recovery pattern was observed in the histopathological structure, mucin secretion, water channel expression and gastrointestinal hormones secretion in the transverse colon; expressions of muscarinic acetylcholine receptors M2/M3 (mAChR M2/M3) and their mediators on muscarinic cholinergic regulation were significantly recovered. Taken together, these results provide the first evidence that TEE stimulates oxidative stress modulation and muscarinic cholinergic regulation when exerting its laxative effects in chronic constipation models. 10.1371/journal.pone.0246363
    Strains Relieve Loperamide-Induced Constipation via Different Pathways Independent of Short-Chain Fatty Acids. Wang Gang,Yang Shurong,Sun Shanshan,Si Qian,Wang Linlin,Zhang Qiuxiang,Wu Gaojue,Zhao Jianxin,Zhang Hao,Chen Wei Frontiers in cellular and infection microbiology Increasing researches have confirmed the relationship between slow-transit constipation and gut microbiota dysbiosis. Many population and animal experiments have identified probiotics as effectors for the relief of constipation symptoms, but the specific mechanism remains unclear. In this intervention study, strains isolated from five different sources were administered to mice with loperamide-induced constipation, and the impacts of these strains on constipation-related indicators were evaluated. All five strains of were found to improve constipation to various degrees. However, contrary to previous studies, the abilities of strains to improve constipation symptoms were not associated with the levels of short-chain fatty acids (SCFAs) in the colon. The effects of different strains of on constipation relief were associated with different aspects of the GI tract, including gastrointestinal regulatory peptides, neurotransmitters, neurotrophic factors, and gut microbiota. The findings of this study demonstrate that strains can alleviate constipation-related symptoms via different pathways independent of SCFAs regulation. This study yields a new perspective for clinical use of probiotics to better improve constipation symptoms, by combining strains with different mechanisms for alleviation of constipation. 10.3389/fcimb.2020.00423
    [Emotional behavior disorders in rats during the formation of a generator of pathologically enhanced excitation in the basomedial nuclei of the amygdaloid complex]. Kryzhanovskiĭ G N,Rodina V I Biulleten' eksperimental'noi biologii i meditsiny Microinjections of kainic acid and ferrous sulfate into basomedial nuclei of both amygdalae resulted in the formation of the generator of pathologically enhanced excitation (GPEE), as evidenced by the epileptical activity (EpA) registered in both nuclei. EpA of different intensity and pattern could be retained for more than three weeks. Hyperactive basomedial nuclei played the role of a primary pathological determinant which caused the complex of emotional and behavioural disorders. Continuous motor depression at the early stages alternated pathologically enhanced activity at the later stages. A number of signs could be considered as the evidence of the affective disorders (motivation suppression, enhanced irritation, anxious excitation). Stereotype behaviour, immobility, rigidity, different types of vegetative disorders (ptosis, constipation, piloerection, loss of weight, respiratory arrhythmia, dystrophic symptoms) were observed in most animals. The emotional, behavioural and vegetative disorders described are compared to the manifestations of the depressive syndrome.
    Activation of prostaglandin EP receptors by lubiprostone in rat and human stomach and colon. Bassil A K,Borman R A,Jarvie E M,McArthur-Wilson R J,Thangiah R,Sung E Z H,Lee K,Sanger G J British journal of pharmacology BACKGROUND AND PURPOSE:Lubiprostone (Amitiza), a possible ClC-2 channel opener derived from prostaglandin E(1) and indicated for the treatment of constipation, increases chloride ion transport and fluid secretion into the intestinal lumen. As lubiprostone may also directly modulate gastrointestinal motility, we investigated its actions and the possible involvement of prostaglandin EP receptor activation on rat and human isolated gastrointestinal preparations. EXPERIMENTAL APPROACH:Rat and human isolated preparations were mounted in tissue baths for isometric recording. The effects of lubiprostone on muscle tension and on electrically stimulated, neuronal contractions were investigated in the absence and presence of EP receptor antagonists. KEY RESULTS:In rat and human stomach longitudinal muscle, lubiprostone induced a contraction (pEC(50) of 7.0+/-0.0, n=4 and 6.4+/-0.2, n=3, respectively), which was inhibited by pretreatment with the EP(1) receptor antagonist, EP(1)A 300 nM (pEC(50) reduced to 6.2+/-0.2, n=6), but not by the EP(3) or EP(4) receptor antagonists (L-798106 and GW627368X, respectively, 1 microM, P>0.05). Lubiprostone also reduced electrically stimulated, neuronal contractions in rat and human colon circular muscle preparations (pIC(50) of 8.9+/-0.4, n=7 and 8.7+/-0.9, n=6, respectively), an effect mediated pre-junctionally. This effect was reduced by the EP(4) receptor antagonist (pIC(50) of 6.7+/-1.1, n=7 and 7.7+/-0.4, n=6, respectively) but not by EP(1) or EP(3) receptor antagonists. CONCLUSIONS AND IMPLICATIONS:In rats and humans, lubiprostone contracts stomach longitudinal muscle and inhibits neuronally mediated contractions of colon circular muscle. Experiments are now needed to determine if this additional activity of lubiprostone contributes to its clinical efficacy and/or side-effect profile. 10.1038/bjp.2008.84
    Laxative effect of peanut sprout extract. Seo Ji Yeon,Kim Seong Soon,Kim Hyo Jung,Liu Kwang-Hyeon,Lee Hak-Yong,Kim Jong-Sang Nutrition research and practice Certain phenolic compounds are known to exhibit laxative properties. Seed sprouts, such as those of peanut, are known to promote de novo biosynthesis of phenolic compounds. This study was conducted to examine the potential laxative properties of 80% (v/v) ethanolic extract of peanut sprout (PSE), which contains a high concentration of phenolic compounds such as resveratrol. For this, SD rats were orally administered PSE while a control group was incubated with saline. Laxative effects were examined in both groups of rats. Constipation induced by loperamide in SD rats was improved by administration of PSE. Constipated rats showed increased intestinal movement of BaSO4 upon administration of PSE compared to the control, and the groups administered 100 or 1,000 mg PSE/kg bw were not significantly different in transit time of the indicator. However, colon length was not statistically different among the experimental groups, although it was longer in the group incubated with 1 g PSE/kg bw compared to other groups. Further, there was no significant difference in stool number among the experimental groups. Taken together, these findings show that PSE has a laxative effect in a rat model of loperamide-induced constipation. 10.4162/nrp.2013.7.4.262
    Radiographic dose-dependency study of loperamide effects on gastrointestinal motor function in the rat. Temporal relationship with nausea-like behavior. Vera Gema,Girón Rocío,Martín-Fontelles María Isabel,Abalo Raquel Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society BACKGROUND:Loperamide is a potent mu opioid receptor agonist available over the counter to treat diarrhea. Although at therapeutic doses loperamide is devoid of central effects, it may exert them if used at high doses or combined with drugs that increase its systemic and/or central bioavailability. Recently, public health and scientific interest on loperamide has increased due to a growing trend of misuse and abuse, and consequent reports on its toxicity. Our aim was to evaluate in the rat the effects of increasing loperamide doses, with increasing likelihood to induce central effects, on gastrointestinal motor function (including gastric dysmotility and nausea-like behavior). METHODS:Male Wistar rats received an intraperitoneal injection of vehicle or loperamide (0.1, 1, or 10 mg kg ). Three sets of experiments were performed to evaluate: (a) central effects (somatic nociceptive thresholds, immobility time, core temperature, spontaneous locomotor activity); (b) general gastrointestinal motility (serial X-rays were taken 0-8 hours after intragastric barium administration and analyzed semiquantitatively, morphometrically, and densitometrically); and (c) bedding intake (a rodent indirect marker of nausea). Animals from sets 1 and 3 were used to evaluate gastric dysmotility ex vivo at 2 and 4 hours after administration, respectively. KEY RESULTS:Loperamide significantly induced antinociception, hypothermia, and hypolocomotion (but not catalepsy) at high doses and dose-dependently reduced gastrointestinal motor function, with the intestine exhibiting higher sensitivity than the stomach. Whereas bedding intake occurred early and transiently, gastric dysmotility was much more persistent. CONCLUSIONS AND INFERENCES:Our results suggest that loperamide-induced nausea and gastric dysmotility might be temporally dissociated. 10.1111/nmo.13621
    Comparison between partial agonist (ME3412) and antagonist (alosetron) of 5-hydroxytryptamine 3 receptor on gastrointestinal function. Kawano K,Mori T,Fu L,Ito T,Niisato T,Yoshida S,Shiokawa S,Sato Y,Murakami H,Shishikura T Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society Therapeutic use of 5-hydroxytryptamine 3 (5-HT(3)) receptor antagonists for diarrhoea-predominant irritable bowel syndrome may be accompanied by constipation. We hypothesized that ME3412, 5-chloro-2-(1,4-diazacycloheptan-1-yl)-7-methylbenzoxazole, a novel partial agonist of the 5-HT(3) receptor, would minimize constipation without reducing antidiarrhoeal activity. Receptor binding studies showed that ME3412 is highly selective for the human 5-HT(3) receptor (K(i) = 1.51 nmol L(-1)). A 5-HT(3) receptor agonist, 2-methyl-5-HT, caused contractile response in the isolated guinea-pig ileum and accelerated secretion in the guinea-pig colonic mucosal preparation. ME3412 and 5-HT(3) receptor antagonist, alosetron, antagonized the 2-methyl-5-HT-induced responses with similar potency in insurmountable and surmountable manner, respectively. ME3412 caused weak agonism in isolated ileum strips and also in the colonic mucosa with intrinsic activity of 0.09 and 0.59, respectively. In conscious dogs, alosetron (3 microg kg(-1) i.v.) suppressed the migrating motor complex (MMC), whereas a relatively high dose (300 microg kg(-1)) of ME3412 was required for inhibition of MMC. ME3412 and alosetron suppressed 5-HT induced-diarrhoea in mice. In contrast, ME3412 did not significantly affect colonic propulsion compared with alosetron. These results imply that the partial agonist may relieve diarrhoea with low risk of inducing constipation. 10.1111/j.1365-2982.2004.00622.x
    Traditional Chinese formula, lubricating gut pill, stimulates cAMP-dependent CI(−) secretion across rat distal colonic mucosa. Wu Dazheng,Zhou Jiyan,Wang Xinhong,Cui Bo,An Rui,Shi Hailian,Yuan Jianye,Hu Zhibi Journal of ethnopharmacology AIM OF THE STUDY:Lubricating gut pill (LGP), a traditional Chinese formula, had been conformed to improve the loperamide-induced rat constipation by stimulation of Cl(-) secretion, but its mechanism has not been fully explored. Thus, the purpose of this study was to identify the action sites of LGP-stimulated Cl(-) secretion across rat distal colonic mucosa. MATERIALS AND METHODS:Rat distal colonic mucosa was mounted in Ussing chambers and short circuit current (I(SC)), apical Cl(-) current and basolateral K(+) current were recorded. Intracellular cyclic adenosine monophosphate (cAMP) content and protein kinase A (PKA) activity were determined with ELISA kit and the non-radioactive PepTag test, respectively. RESULTS:LGP at 800μg/ml elicited a sustained increase in Cl(-) secretory response, which was inhibited by CFTR(inh)172, a cystic fibrosis transmembrane conductance regulator (CFTR) inhibitor. Permeabilizing apical membrane with nystatin revealed that LGP-stimulated basolateral K(+) current was significantly inhibited by KCNQ1 K(+) channel inhibitor chromanol 293B. LGP-stimulated I(SC) was markedly reduced by pretreatment with cis-N-[2-phenylcyclopentyl]-azacyclotridec-1-en-2amine (MDL-12,330A) and N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide (H-89), but not with inhibitors of Ca(2+)-dependent signaling pathway. Treatment of tissue with LGP resulted in an increase in intracellular cAMP level and the activation in protein kinase A. The E-prostanoid(4) (EP)(4) receptor antagonist L-161,982 completely eliminated LGP-induced response. CONCLUSIONS:The results showed that LGP enhances Cl(-) and fluid secretion via prostanoid receptor signaling and also cAMP and protein kinase A pathway, subsequently triggering the activation of apical Cl(-) channels mostly CFTR and basolateral cAMP-dependent K(+) channel. 10.1016/j.jep.2010.12.031
    Effects of lactulose on renal function and gut microbiota in adenine-induced chronic kidney disease rats. Sueyoshi Miyu,Fukunaga Masaki,Mei Mizue,Nakajima Atsushi,Tanaka Gaku,Murase Takayo,Narita Yuki,Hirata Sumio,Kadowaki Daisuke Clinical and experimental nephrology BACKGROUND:Constipation is frequently observed in patients with chronic kidney disease (CKD). Lactulose is expected to improve the intestinal environment by stimulating bowel movements as a disaccharide laxative and prebiotic. We studied the effect of lactulose on renal function in adenine-induced CKD rats and monitored uremic toxins and gut microbiota. METHODS:Wistar/ST male rats (10-week-old) were fed 0.75% adenine-containing diet for 3 weeks to induce CKD. Then, they were divided into three groups and fed as follows: control, normal diet; and 3.0- and 7.5-Lac, 3.0% and 7.5% lactulose-containing diets, respectively, for 4 weeks. Normal diet group was fed normal diet for 7 weeks. The rats were observed for parameters including renal function, uremic toxins, and gut microbiota. RESULTS:The control group showed significantly higher serum creatinine (sCr) and blood urea nitrogen (BUN) 3 weeks after adenine feeding than at baseline, with a 8.5-fold increase in serum indoxyl sulfate (IS). After switching to 4 weeks of normal diet following adenine feeding, the sCr and BUN in control group remained high with a further increase in serum IS. In addition, tubulointerstitial fibrosis area was increased in control group. On the other hand, 3.0- and 7.5-Lac groups improved sCr and BUN levels, and suppressed tubulointerstitial fibrosis, suggesting preventing of CKD progression by lactulose. Lac groups also lowered level of serum IS and proportions of gut microbiota producing IS precursor. CONCLUSION:Lactulose modifies gut microbiota and ameliorates CKD progression by suppressing uremic toxin production. 10.1007/s10157-019-01727-4
    Metabolomics study on the therapeutic effect of the Chinese herb pair Fructus Aurantii Immaturus and Rhizoma Atractylodis Macrocephalae in constipated rats based on UPLC-Q/TOF-MS analysis. Yan Shuai,Hao Min,Yang Huiju,Sun Mingming,Wu Bensheng,Yue Yinzi,Wang Xiaopeng Annals of palliative medicine BACKGROUND:In China, Zhishi (Aurantii Fructus Immaturus) - Baizhu (Atractylodis Macrocephalae Rhizoma) is a well-known herb pair used to treat gastrointestinal motility disorders for thousands of years, and it has especially shown a definite advantage in the treatment of slow transit constipation (STC). However, the mechanism of Zhishi-Baizhu (ZSBZ) in the treatment of STC remains unclear. In this study, plasma metabolomics research combined with metabolic pathway analysis has been used to illuminate the potential mechanism of its effects against STC. METHODS:Parameters of intestinal transit ratio, plasma motilin (MTL), substance P (SP), adenosine triphosphate (ATP), histological alteration of the colon and MLCK expression in the colon were detected to evaluate the effects with respect to STC. Principal component analysis (PCA) was used to investigate the global metabolite alterations, while orthogonal partial least squares discriminant analysis (OPLS-DA) and t-test were used to filter potential metabolite markers. Moreover, metabolic pathway analysis was employed. RESULTS:Oral administration of ZSBZ significantly prevented the development of STC. It increased the expression of MTL and SP in serum, as well as the expression of ATP and MLCK in the colon. ZSBZ administration alleviated symptoms in loperamide-induced constipated rats, evidenced by the increase of intestinal transit ratio. Futhermore, 9 potential biomarkers of STC were screened, and the levels were all reversed to different degrees after ZSBZ administration. Metabolic pathway analysis showed that the improvement of STC by ZSBZ was mainly related to caffeine and vitamin B6 metabolism. CONCLUSIONS:Our study identifies the metabolic networks of constipated rats and demonstrates the efficacy of this metabolomics approach to systematically study the therapeutic effects of ZSBZ on constipation. 10.21037/apm-20-280
    Ileocecal Valve Removal Reverses the Constipating Effects of Loperamide in Rats. Mentessidou Anastasia,Livani Anastasia,Chrousos George,Mirilas Petros The Journal of surgical research BACKGROUND:Previous evidence associating ileocecal valve removal (ICVR) with a reduced risk of fecal impaction of the ileocecum in cystic fibrosis indicated possible benefits from ileocecal valve loss in disorders with inhibited proximal colon transit caused by fecal dehydration and hypoperistalsis. We aimed to investigate the ability of ICVR in reversing fecal impaction in a loperamide-induced model of a similar pattern of inhibited proximal colon transit in rats. MATERIALS AND METHODS:Thirty pubertal Sprague-Dawley rats were rendered constipated with subcutaneous loperamide treatment (1 mg/kg/d) for 7 d. On day four, rats were allocated to groups: ICVR (n = 12), total colectomy (TC, n = 9), and sham operation (SO, n = 9). Fecal pellet number and consistency were assessed daily. On day seven, all rats were gavaged with barium. Two hours later, intestinal transit ratio (distance of barium head from the pylorus adjusted for small intestine length) and adjusted (for total intestine length) barium-to-anus distance were assessed. RESULTS:ICVR showed higher transit ratio and shorter barium-to-anus distance, that is, faster transit, than SO (P < 0.0001); differences between ICVR and TC were not significant (P > 0.06). Furthermore, ICVR and TC showed similar reduction in hard feces, compared with SO (P < 0.0001). TC showed higher diarrhea rate than ICVR (P < 0.0001). CONCLUSIONS:ICVR led to an effective, similar to TC, reversal of the constipating effects of loperamide and, unlike TC, was not associated with diarrhea. Our findings support the idea that ICVR might be beneficial in disorders with inhibited proximal colon transit resulting from fecal dehydration and hypoperistalsis, such as refractory cystic fibrosis-related intestinal obstruction. Potential clinical implications merit further study. 10.1016/j.jss.2020.05.002
    Laxative and antioxidant effects of ramie ( L) leaf extract in experimental constipated rats. Lee Hyun-Joo,Choi Eun Joo,Park Sihoon,Lee Jae-Joon Food science & nutrition Ramie leaf ( L.) is rich in cellulose, polyphenol compounds, vitamin C, and minerals. The leaves of this plant, which are used for medicinal purposes, have long been reported to have anti-inflammatory, antioxidant, anticolitis, and antidiabetic effects. We investigated the protective effects of ramie leaf ethanol extract (RLE) against loperamide-induced constipation and oxidative stress in rats. Male Sprague-Dawley rats were administered 200 or 400 mg/kg body weight of RLE (RLEL and RLEH groups) by gavage, while normal (NOR) and control (CON) rats received saline. Loperamide (4.0 mg/kg, twice per day) was injected subcutaneously to induce constipation in RLEL, RLEH, and CON groups. Total fecal number, wet weight, and water content decreased, while the total number of loperamide-induced fecal pellets in the distal colon increased with administration of RLE in a dose-dependent manner. Gastrointestinal transit time was more greatly reduced in RLE-treated groups than in the CON group. Serum total cholesterol (TC) level, as well as alanine aminotransferase (ALT) and alkaline phosphatase (ALP) activity, was significantly lower in both RLEL and RLEH groups compared with the CON group. Intestinal mucosa malondialdehyde (MDA) and hydrogen peroxide (HO) production decreased significantly in a dose-dependent manner in the RLE-treated groups. Loperamide decreased the antioxidant enzyme activity, including that of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), while RLE administration increased the antioxidant activity. These results suggest that RLE exerts potent laxative and antioxidant effects in model rats with loperamide-induced constipation. 10.1002/fsn3.1619
    Effect of Tong Xie Yao Fang on endogenous metabolites in urine of irritable bowel syndrome model rats. Zhao Xue-Ying,Wang Jian-Wei,Yin Yue,Li Kai,Zhang Miao,Yan Fu-Ping World journal of gastroenterology BACKGROUND:Tong Xie Yao Fang is a representative traditional Chinese prescription for the treatment of liver and spleen deficiency, abdominal pain and diarrhea. It has a unique function in the treatment of gastrointestinal dysfunction including irritable bowel syndrome (IBS), is a common functional bowel disease. Its main symptoms are recurrent abdominal pain, diarrhea, constipation or alternations between diarrhea and constipation. There are obvious differences in metabolites between TCM syndromes. By comparing the body fluid metabolism maps of model animals, metabolomics can discover disease biomarkers, analyze the differences in metabolic pathways and understand the pathological process and the metabolic pathways of substances in the body. Thus, the evaluation of animal models tends to be comprehensive and objective. This may provide further understanding between the interaction between Tong Xie Yao Fang and the IBS model. AIM:To evaluate the effect of Tong Xie Yao Fang on IBS rats by using metabolomics method. METHODS:Wistar rats were used to establish IBS models, and then randomly divided into four groups: A model control group and three Tong Xie Yao Fang treatment groups (high, medium and low doses). A normal, non-IBS group was established. The rats were treated for 2 wk. On days 0 and 14 of the experimental model, urine was collected for 12 h and was analyzed by ultra-performance liquid chromatography quadrupole time-of-flight mass spectrometry. Nine potential biomarkers were identified, and six major metabolic pathways were found to be related to IBS. RESULTS:In the study of metabonomics, nine potential biomarkers including L-serine, 4-methylgallic acid, L-threonine, succinylacetone, prolyl-hydroxyproline, valyl-serine, acetyl citrate, marmesin rutinoside and 5-hydroxy-L-tryptophan were identified in urine, which were assigned to amino acids, organic acids, succinyl and glycosides. Furthermore, the metabolic pathway of L-serine, L-threonine and 5-hydroxy-L-tryptophan was found in the Kyoto Encyclopedia of Genes and Genomes, which mainly involved the metabolism of cysteine and methionine, vitamin B6 metabolism, serotonin synapse, tryptophan metabolism, sphingolipid metabolism, digestion, absorption of protein and amino acid metabolism. These pathways are related to intestinal dysfunction, inflammatory syndrome, nervous system dysfunction and other diseases. CONCLUSION:Tong Xie Yao Fang has pharmacological effects on IBS, and its mechanism may be related to the metabolism of the nine potential biomarkers identified above in urine. 10.3748/wjg.v25.i34.5134
    Pharmacological Evaluation of Gut Modulatory and Bronchodilator Activities of Achyranthes aspera Linn. Rahman Hafiz Muhammad Abdur,Bashir Samra,Mandukhail Safur Rehman,Huda Sohaib,Gilani Anwarul Hassan Phytotherapy research : PTR Achyranthes aspera L. is traditionally used to relieve constipation, diarrhea, and asthma. Its crude extract (Aa.Cr) was evaluated through in vivo and ex vivo experiments to rationalize these medicinal uses of A. aspera and to provide their scientific basis. Aa.Cr, at 3 and 10 mg/kg, increased fecal output, similar to castor oil, whereas at 30, 100, 300, and 700 mg/kg, it protected against castor oil-induced diarrhea in mice when administered orally. Aa.Cr caused spasmogenic effect on rabbit jejunum and guinea pig ileum preparations, which was partially inhibited by atropine while completely blocked by cyproheptadine preincubation. Aa.Cr also relaxed high K (80 mM)-induced contraction in rabbit jejunum. Aa.Cr inhibited CCh (100 μg/kg)-induced bronchospasm in rats, similar to aminophylline. Like dicyclomine, Aa.Cr relaxed high K and CCh (1 μM)-induced contractions in guinea pig trachea and caused rightwards parallel shift of CCh concentration-response curves at the lower concentrations followed by non-parallel shift at the higher concentrations. On activity-directed fractionation, spasmogenic and spasmolytic activities of Aa.Cr were concentrated in aqueous and organic fraction, respectively. This study suggests the presence of dose-specific laxative and antidiarrheal effects in A. aspera, possibly mediated through cyproheptadine-sensitive receptors and dual cholinergic and calcium channel blockade, respectively. The latter combination is also a suggested mechanism underlying its bronchodilator effect. Copyright © 2017 John Wiley & Sons, Ltd. 10.1002/ptr.5907
    Formulation of traditional Chinese medicine and its application on intestinal flora of constipated rats. Li Sihan,He Youcheng,Zhang Haiou,Zheng Rong,Xu Ruoying,Liu Qihong,Tang Shuihua,Ke Xiao,Huang Minghan Microbial cell factories In this study, the self-extracted constipation treatment of traditional Chinese medicine extracts was applied to constipated rats. To explore the mechanism and role of the Chinese medicine for the treatment of constipation, the 16S rRNA sequencing and qRT-PCR technology were used to analyze the intestinal flora. We found that the relative abundance of Firmicutes with constipation was significantly higher accounted for 86.7%, while the gut microbiota was significantly changed after taking a certain dose of Chinese medicine, greatly increased the relative abundance of Lactobacillus accounted for 23.1%, enhanced the symbiotic relationships of Lactobacillus with other intestinal flora. The total copies of intestinal bacteria in the constipated rats decreased after taking the traditional Chinese medicine. Finally, this study results provides a theoretical basis for the treatment and understand the mechanism and effect of traditional Chinese medicine on rate constipation. 10.1186/s12934-020-01473-3
    Effects of Fermented Milk with Mixed Strains as a Probiotic on the Inhibition of Loperamide-Induced Constipation. Kim Byoung-Kook,Choi In Suk,Kim Jihee,Han Sung Hee,Suh Hyung Joo,Hwang Jae-Kwan Korean journal for food science of animal resources To investigate the effects of a single bacterium and a mixture of bacteria as probiotics in loperamide-treated animal models, loperamide (3 mg/kg) was administered to SD rats to induce constipation. The individual lactic acid bacterial doses, (EF), (LA), (ST), (BB), (BL), (PP), and a mixture of the bacteria were orally administered to loperamide-induced constipated rats at a concentration of 10 CFU/kg for 14 days. The weights and water contents of their stools were found to be significantly higher in PP, CKDB (mixture of 5 strains except PP), and CKDBP (CKDB+PP) groups than in the normal (constipation not induced) and the control (constipation-induced) groups (<0.05). The intestinal transit ratio was significantly higher in all probiotic-treated groups than in the control group, and was the highest in the CKDBP group (<0.05). The mucosal length and mucus secretion were significantly improved in all probiotic-treated-groups, as compared to that in the control group, and the CKDBP group was found to be the most effective according to immunohistochemistry (IHC) staining and total short chain fatty acid content analysis (<0.05). Lastly, PP, CKDB, and CKDBP showed relatively higher sp. ratios of 61.94%, 60.31% and 51.94%, respectively, compared to the other groups, based on metagenomic analysis. 10.5851/kosfa.2017.37.6.906
    Maren Pills Improve Constipation via Regulating AQP3 and NF-B Signaling Pathway in Slow Transit Constipation In Vitro and In Vivo. Zhan Yu,Tang Xuegui,Xu Hong,Tang Shiyu Evidence-based complementary and alternative medicine : eCAM Background:Maren pills have been used to treat constipation. Aquaporin 3 (AQP3) plays a vital role in regulating water transfer in the colon. It has been reported that the downregulation of AQP3 can regulate liquid water metabolism and intestinal permeability in irritable bowel syndrome (IBS) rats' colon via NF-B pathway. In this study, we investigated whether the laxative effect of Maren pills is associated with the regulation of AQP3 and NF-B signaling pathway in the colon. Methods:The compound diphenoxylate suspension-induced STC rats received Maren pills intragastrically for 1 consecutive week to evaluate the laxative effect of Maren pills involving the regulation of AQP3 and NF-B signaling pathway. Moreover, human intestinal epithelial cells (HT-29) were treated with drug serum to obtain in vitro data. Results:Our results revealed that treatment with Maren pills increased the stool number, moisture content of feces, and intestinal transit rate in a dose-dependent manner. Maren pills significantly increased the AQP3, fibrosis transmembrane conductance regulator (CFTR), and protein kinase A (PKA) proteins in the colon of rats and in HT-29 cells. Mechanistically, Maren pills obviously inhibited the activation of NF-B pathway in the colon of rats and in HT-29 cells. Conclusion:These results suggest that the laxative effect of Maren pills is associated with the increased expression of AQP3 by downregulating NF-B signal pathway. 10.1155/2020/9837384
    Toxicological evaluation of aqueous extract of Aloe ferox Mill. in loperamide-induced constipated rats. Wintola O A,Sunmonu T O,Afolayan A J Human & experimental toxicology Aloe ferox Mill. is a widely used medicinal plant in South Africa for the treatment of many ailments including constipation. The present study evaluated the toxicological effect of aqueous leaf extract of the herb at 50, 100 and 200 mg/kg body weight for 7 days on the haematological parameters as well as liver and kidney function indices in loperamide-induced constipated rats. The extract did not cause any significant (p > 0.05) effect on the kidney and liver-body weight ratio as well as the kidney function indices including serum levels of creatinine, uric acid, urea, calcium and potassium ions at all the dosages investigated. Whereas the serum levels of total protein, albumin, bilirubin and gamma glutamyl trasferase (GGT) were not affected, the elevated activities of alkaline phosphatase (ALP), alanine transaminase (ALT) and aspartate transaminase (AST) in the untreated constipated animals were normalized following treatment with extract. The data obtained with respect to the haematological analysis indicated that the extracts had no significant (p > 0.05) effect on the haematological parameters with the exception of lymphocyte count which was increased in the untreated constipated rats. This was however attenuated after administering the herb. The available evidence in this study suggests that A. ferox may be safe as an oral remedy for constipation. Generally, the effect of the extract compared favourably well with senokot, a recommended drug for the treatment of constipation. 10.1177/0960327110372647
    Lactic acid fermentation of germinated barley fiber and proliferative function of colonic epithelial cells in loperamide-induced rats. Jeon Jeong Ryae,Choi Joon Hyuk Journal of medicinal food To develop a functional food from the dietary fiber fraction of germinated barley (Hordeum vulgare L.) (GBF), lactic acid fermentation was attempted using Lactobacillus acidophilus, Streptococcus thermophilus, and Bifidobacterium bifidus. The quality characteristics of the lactic acid-fermented product and its effect on gastrointestinal function in an animal model were examined. The anaerobic fermentation of 1% and 2% GBF yielded lactic acid bacteria at 8.9 +/- 1.0 x 10(8) and 1.6 +/- 0.2 x 10(9) colony-forming units/mL, and it was considered acceptable for consumption by sensory assessment. To determine the effect on gastrointestinal function, Sprague-Dawley rats were fed with three types of diets: a normal chow diet and chow diets supplemented with 10% lactic acid bacteria or a yogurt fermented with 2% GBF (GBFY). The rats fed GBFY for 6 weeks gained less body weight, excreted more fecal mass, and had improved gastrointestinal transit as examined with barium sulfate. The effect of GBFY on colonic epithelial proliferation was investigated through loperamide (LPM)-induced constipation in rats. The rats fed with GBFY for 6 weeks were intraperitoneally administered LPM twice daily for 7 days. GBFY supplementation decreased fecal excretion and moisture content in feces and depleted goblet cells as observed by hematoxylin and eosin stain. However, the rats supplemented with GBFY prior to the LPM administration had enhanced bowel movement, mucin secretion, and production of short-chain fatty acids compared with values for the LPM-alone group. Immunohistochemistry revealed that the GBFY supplement increased the numbers of nuclei stained positively for Ki-67 and extended from the base to the middle zone of crypts. These results indicate that GBFY alleviates constipation via the proliferation of the colonic crypts in LPM-administered rats. 10.1089/jmf.2009.1307
    Synergistic effect of fermented rice extracts on the probiotic and laxative properties of yoghurt in rats with loperamide-induced constipation. Choi Jae-Suk,Kim Joo Wan,Kim Ki-Young,Lee Jong-Kwang,Sohn Jae Hak,Ku Sae-Kwang Evidence-based complementary and alternative medicine : eCAM Aim. The objective was to evaluate the synergistic effects of fermented rice extracts (FRe) on the laxative and probiotic properties of yoghurt in rats with loperamide-induced constipation. Methods. After constipation induction, yoghurt containing FRe (BFRe; 0.05%, 0.1%, or 1%) was administered orally once per day for 6 days. Results. Loperamide treatment caused marked decreases in fecal pellet numbers and water content discharged, as well as in the surface mucosal thickness of the colonic lumen, intestinal charcoal transit ratio, thickness, and number of mucous-producing goblet cells in the colonic mucosa, whereas it increased the remnant fecal pellet number and the mean diameter of the colonic lumen. However, this loperamide-induced constipation was ameliorated by treatment with FRe, yoghurt single formula, or 0.05%, 0.1%, or 1% BFRe (10 mL/kg). Additionally, the viable numbers of Lactobacillus in the cecal contents and feces were markedly higher than those in constipated rats. Moreover, greater probiotic and laxative effects were detected in BFRe-treated rats than in rats treated with equivalent doses of yoghurt or FRe single formula. Conclusion. The results suggest that addition of FRe to liquid yoghurt will enhance the probiotic and beneficial laxative effects of yoghurt in the digestive tract, without causing side effects. 10.1155/2014/878503
    Aqueous Extracts of Promoted Intestinal Motility in Loperamide-Induced Constipation Rats by Ameliorating the Interstitial Cells of Cajal. Yan Shuai,Yue Yin-Zi,Wang Xiao-Peng,Dong Hong-Li,Zhen Shu-Guang,Wu Ben-Sheng,Qian Hai-Hua Evidence-based complementary and alternative medicine : eCAM Traditional Chinese medicine was reported to have good effects in treating functional constipation. This work attempted to prove the effects of aqueous extracts of (AEHC) on STC treatment and to determine the possible mechanisms by a loperamide-induced slow transit constipation (STC) model. HPLC was performed for identification and confirmation of the bioactive components in the AEHC. It was found that AEHC attenuated STC responses based on increased fecal quantity, moisture content, and intestinal transit rate, as well as serum levels of GAS, MTL, SS, and CGRP. The protein and mRNA levels of c-kit, a labeling of interstitial cells of Cajal (ICC), also increased. Meanwhile, only the protein level of SCF, a ligand of c-kit, increased. The analysis of our data suggested that AEHC could obviously improve the function of ICC via a signaling pathway involving PI3K, SCF, and c-kit and enhance colonic motility indices such as GAS, MTL, SS, and CGRP. It is interesting to note that AEHC appeared to be effective on constipation, so further experiments are necessary to clarify the exact mechanisms involved. 10.1155/2017/6236904
    Hesperidin Improves Colonic Motility in Loeramide-Induced Constipation Rat Model via 5-Hydroxytryptamine 4R/cAMP Signaling Pathway. Wu Minna,Li Youran,Gu Yunfei Digestion Fructus has motivation effect on gastrointestinal tract. Hesperidin is extracts of Fructus, and we attempted to prove its effects on improving the gastrointestinal transmission function and determine the possible mechanisms by a loperamide-induced slow transit constipation (STC) model. Constipation phenotypes were measured in rats with Lop-induced constipation after treatment with hesperidin. The amounts and water content of stool were significantly higher in the hesperidin-treated group than the loperamide-induced model group, whereas food intake was maintained at constant levels. Moreover, intestinal transit rate was increased in the treatment group of hesperidin. Histological alteration was detected by H&amp;E staining, we found that the colon smooth muscle cells and neuron cells of the rats were increased, and the infiltration of inflammatory cells was decreased in the hesperidin-treated group compared with the loperamide-induced model group. 5-Hydroxytryptamine (5-HT) receptor4 fluorescence intensity and intracellular-free calcium ions in colon tissue were increased, and relative protein of cAMP/PKA pathway and p-cAMP response component-binding protein (CREB) pathway were upregulated in the hesperidin-treated group compared with the loperamide-induced model group. Further, SMCs from colon tissue of rats were cultured and identified. We found hesperidin could significantly promote tegaserod-induced increase of 5-HTR4 fluorescence intensity, intracellular calcium ions, relative protein of cAMP/PKA pathway and p-CREB pathway, and cell proliferation and inhibit GR113808-induced decrease of 5-HTR4 fluorescence intensity, 5-HTR4 pathway-related proteins (ADCY3, cAMP, PKA, and p-CREB), intracellular calcium ions, and cell proliferation. The analysis of our data suggested that hesperidin could obviously improve the gastrointestinal transmission function in loperamide-induced STC rat model via increasing the 5-HTR4 and intracellular-free calcium ions to enhance the expression of relative protein of cAMP/PKA pathway and p-CREB pathway. Hesperidin could be used in the treatment of STC, and our data not only provide experimental basis for the treatment of STC in hesperidin but also provides a theoretical reference for clinical treatment. 10.1159/000501959
    Ameliorative effects of atractylodin on intestinal inflammation and co-occurring dysmotility in both constipation and diarrhea prominent rats. Yu Changchun,Xiong Yongjian,Chen Dapeng,Li Yanli,Xu Bin,Lin Yuan,Tang Zeyao,Jiang Chunling,Wang Li The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology Intestinal disorders often co-occur with inflammation and dysmotility. However, drugs which simultaneously improve intestinal inflammation and co-occurring dysmotility are rarely reported. Atractylodin, a widely used herbal medicine, is used to treat digestive disorders. The present study was designed to characterize the effects of atractylodin on amelioration of both jejunal inflammation and the co-occurring dysmotility in both constipation-prominent (CP) and diarrhea-prominent (DP) rats. The results indicated that atractylodin reduced proinflammatory cytokines TNF-α, IL-1β, and IL-6 in the plasma and inhibited the expression of inflammatory mediators iNOS and NF-kappa B in jejunal segments in both CP and DP rats. The results indicated that atractylodin exerted stimulatory effects and inhibitory effects on the contractility of jejunal segments isolated from CP and DP rats respectively, showing a contractile-state-dependent regulation. Atractylodin-induced contractile-state-dependent regulation was also observed by using rat jejunal segments in low and high contractile states respectively (5 pairs of low/high contractile states). Atractylodin up-regulated the decreased phosphorylation of 20 kDa myosin light chain, protein contents of myosin light chain kinase (MLCK), and MLCK mRNA expression in jejunal segments of CP rats and down-regulated those increased parameters in DP rats. Taken together, atractylodin alleviated rat jejunal inflammation and exerted contractile-state-dependent regulation on the contractility of jejunal segments isolated from CP and DP rats respectively, suggesting the potential clinical implication for ameliorating intestinal inflammation and co-occurring dysmotility. 10.4196/kjpp.2017.21.1.1
    Laxative effects of Liriope platyphylla are tightly correlated with suppression of endoplasmic reticulum stress in loperamide-induced constipation of SD rats. Kim Ji-Eun,Go Jun,Sung Ji-Eun,Lee Hyun-Ah,Seo Eun-Ji,Yun Woo-Bin,Hwang Dae-Youn Laboratory animal research A dysfunction of endoplasmic reticulum (ER) stress response can result in various diseases, including cancer, inflammation, diabetes and neurodegenerative disorders. To investigate whether ER stress response can play an essential role in the induction and treatment of chronic constipation, alterations in the key parameters for ER stress were measured in loperamide (Lop) induced constipation Sprague Dawley (SD) rats treated with aqueous extracts of Liriope platyphylla (AEtLP), which has been shown to have a laxative effect. Symptoms of chronic constipation including alteration of stool parameters and the transverse colon's structure were successfully induced by Lop treatment. Laxative effects such as enhancement of stools parameters, recovery of the mucosa thickness, increased muscle thickness and recovery of flat luminal surface were also observed in the Lop+AEtLP treated group. Furthermore, enhancement of eukaryotic initiation factor 2 alpha (eIF2α) phosphorylation and inositol-requiring enzyme 1 beta (IRE1β) expression, key indicators for ER stress, that were observed in the Lop+vehicle treated group were significantly recovered in the Lop+AEtLP treated group, although the phosphorylation level of c-Jun N-terminal protein kinase (JNK) remained constant. Moreover, alterations in the transcription level of the marker genes X-box binding protein 1 (XBP-1) and growth arrest and DNA damage-inducible protein (GADD34) were similar to those of eIF2α and IRE1β. However, their level was slightly or completely recovered after AEtLP treatment. Overall, this study provides the first evidence that ER stress response may be tightly correlated with chronic constipation induced by Lop treatment, as well as the laxative effects of AEtLP. 10.5625/lar.2016.32.1.16
    Laxative effects of fermented rice extract in rats with loperamide-induced constipation. Choi Jae-Suk,Kim Joo Wan,Cho Hyung-Rae,Kim Ki-Young,Lee Jong-Kwang,Sohn Jae Hak,Ku Sae-Kwang Experimental and therapeutic medicine Constipation is a common problem in males and females. The aim of the present study was to evaluate the laxative effects of fermented rice extract (FRe) on rats with loperamide-induced constipation. FRe (100, 200 and 300 mg/kg) was administered orally once per day for six days following 1 h loperamide treatment. The laxative effects of FRe were compared with those of sodium picosulfate (S. picosulfate). Following the induction of constipation in the rats, a marked decrease was observed in the fecal pellet number and water content discharged over 24 h, the surface mucus thickness in the colonic lumen, intestinal charcoal transit ratio, thickness of the colonic mucosa and the number of mucus-producing cells, while an increase was observed in the number of fecal pellets remaining in the colonic lumen and their mean diameter, as compared with the normal vehicle control rats. These conditions were significantly alleviated following the administration of the three doses of FRe when compared with the loperamide control group. However, the alleviating effects were lower than those of S. picosulfate, with the exception of the intestinal charcoal transit ratio. Similar effects on the intestinal charcoal transit ratio were detected for the three doses of FRe when compared with the S. picosulfate-treated rats. In conclusion, the results indicated that FRe exhibits a laxative effect without causing diarrhea, as compared with sodium picosulfate; thus, FRe may be effective as a complementary medicine in patients suffering from lifestyle-induced constipation. 10.3892/etm.2014.2030
    Regulation of gastrointestinal hormones during laxative activity of gallotannin-enriched extract isolated from Galla Rhois in loperamide-induced constipation of SD rats. Kim Ji Eun,Kang Mi Ju,Choi Jun Young,Park Jin Ju,Lee Mi Rim,Song Bo Ram,Kim Hye Ryeong,Park Ji Won,Choi Hyeon Jun,Bae Su Ji,Hwang Dae Youn Laboratory animal research Regulation of gastrointestinal hormones have been reported in animal models for constipation undergoing laxative therapy when administered herbal products. We undertook to investigate whether the laxative activity of gallotannin-enriched extracts isolated from Galla Rhois (GEGR) affects the regulation of gastrointestinal hormones, by examining the concentration of four hormones and the activation of their receptors in the loperamide (Lop)-induced constipation model. Stool parameters, including number, weight and water content, were significantly recovered in the Lop+GEGR treated group, relative to the Lop+vehicle treated group; however, food intake and water consumption were maintained at a constant level. Also, a similar recovery was detected for thickness of mucosa, muscle and flat luminal surface in the Lop+GEGR treated group. Furthermore, concentration of the four gastrointestinal hormones evaluated, namely, cholecystokinin (CCK), gastrin (GAS), somatostatin (SS) and motilin (MTL), were lower in the Lop+vehicle treated group than the No treated group, but were remarkably enhanced in the Lop+GEGR treated group. Moreover, the downstream signaling pathway of MTL and SS receptors were recovered after GEGR administration. Results of the present study therefore indicate that the laxative effects of GEGR treatment may be tightly related with the regulation of gastrointestinal hormones in the Lop-induced constipation model. 10.5625/lar.2018.34.4.223
    Comparative pharmacokinetics of rhein in normal and loperamide-induced constipated rats and microarray analysis of drug-metabolizing genes. Hou Mei-Ling,Chang Li-Wen,Lin Chi-Hung,Lin Lie-Chwen,Tsai Tung-Hu Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Rhein is a pharmacological active component found in Rheum palmatum L. that is the major herb of the San-Huang-Xie-Xin-Tang (SHXXT), a medicinal herbal product used as a remedy for constipation. Here we have investigated the comparative pharmacokinetics of rhein in normal and constipated rats. Microarray analysis was used to explore whether drug-metabolizing genes will be altered after SHXXT treatment. MATERIALS AND METHODS:The comparative pharmacokinetics of rhein in normal and loperamide-induced constipated rats was studied by liquid chromatography with electrospray ionization tandem mass spectrometry (LC-MS/MS). Gene expression profiling in drug-metabolizing genes after SHXXT treatment was investigated by microarray analysis and real-time polymerase chain reaction (RT-PCR). RESULTS:A validated LC-MS/MS method was applied to investigate the comparative pharmacokinetics of rhein in normal and loperamide-induced constipated rats. The pharmacokinetic results demonstrate that the loperamide-induced constipation reduced the absorption of rhein. Cmax significantly reduced by 2.5-fold, the AUC decreased by 27.8%; however, the elimination half-life (t1/2) was prolonged by 1.6-fold. Tmax and mean residence time (MRT) were significantly prolonged by 2.8-fold, and 1.7-fold, respectively. The volume of distribution (Vss) increased by 2.2-fold. The data of microarray analysis on gene expression indicate that five drug-metabolizing genes, including Cyp7a1, Cyp2c6, Ces2e, Atp1b1, and Slc7a2 were significantly altered by the SHXXT (0.5 g/kg) treatment. CONCLUSION:The loperamide-induced constipation reduced the absorption of rhein. Since among the 25,338 genes analyzed, there were five genes significantly altered by SHXXT treatment. Thus, information on minor drug-metabolizing genes altered by SHXXT treatment indicates that SHXXT is relatively safe for clinical application. 10.1016/j.jep.2014.07.022
    Traditional Chinese formula, lubricating gut pill, improves loperamide-induced rat constipation involved in enhance of Cl- secretion across distal colonic epithelium. Wu Dazheng,Wang Xinhong,Zhou Jiyan,Yuan Jianye,Cui Bo,An Rui,Hu Zhibi Journal of ethnopharmacology AIM OF THE STUDY:Lubricating gut pill (LGP), a traditional Chinese formula, was widely used for the treatment of chronic constipation, especially in the elderly, in China. However, it is unclear whether LGP-induced laxative and/or lubricating effect is involved in water and electrolytes transport in distal colonic epithelium. MATERIALS AND METHODS:The present study was designed to evaluate the effect of LGP on Cl(-) secretion across rat distal colonic epithelium mounted in Ussing chambers, and on a rat constipation model induced by loperamide, respectively. RESULTS:Application of LGP in the apical side elicited a sustained increase in short circuit current (I(SC)) response in a concentration-dependent manner. Evidence that LGP-stimulated I(SC) was due to Cl(-) secretion is based on inhibition of current by (a) a Na(+)-K(+)-2Cl(-) cotransporter inhibitor bumetanide, (b) removal of Cl(-) ions in bath solution, and (c) the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel blocker DPC, suggesting that a apical cAMP-dependent Cl(-) channel was activated. LGP-stimulated I(SC) was also strongly inhibited by pretreatment with clotrimazole, indicating that the basolateral K(+) channel was also involved in maintaining this cAMP-dependent Cl(-) secretion. Pretreatment of tissues with indomethacin, but not atropine, tetrodotoxin or hexamethonium, inhibited LGP-induced response. In a rat constipation model, oral administration with LGP was significantly restored number of fecal pellets, water content and mucus secretion compared with loperamide-treated group alone. CONCLUSIONS:LGP enhances Cl(-) secretion that is mostly mediated through the release of cyclooxygenase metabolites, by which provided an osmotic force for the subsequent laxative action observed in the rat constipation model. 10.1016/j.jep.2010.05.018
    Effect of dual-type oligosaccharides on constipation in loperamide-treated rats. Han Sung Hee,Hong Ki Bae,Kim Eun Young,Ahn So Hyun,Suh Hyung Joo Nutrition research and practice BACKGROUND/OBJECTIVES:Constipation is a condition that can result from intestinal deformation. Because humans have an upright posture, the effects of gravity can cause this shape deformation. Oligosaccharides are common prebiotics and their effects on bowel health are well known. However, studies of the physiological functionality of a product that contains both lactulose and galactooligosaccharides are insufficient. We investigated the constipation reduction effect of a dual-type oligosaccharide, Dual-Oligo, in loperamide-treated rats. MATERIALS/METHODS:Dual-Oligo consists of galactooligosaccharides (15.80%) and lactulose (51.67%). Animals were randomly divided into four groups, the normal group (normal), control group (control), low concentration of Dual-Oligo (LDO) group, and high concentration of Dual-Oligo (HDO) group. After 7 days of oral administration, fecal pellet amount, fecal weight, water content of fecal were measured. Blood chemistry, short-chain fatty acid (SCFA), gastrointestinal transit ratio and length and intestinal mucosa were analyzed. RESULTS:Dual-Oligo increased the fecal weight, and water content of feces in rats with loperamide-induced constipation. Gastrointestinal transit ratio and length and area of intestinal mucosa significantly increased after treatment with Dual-Oligo in loperamide-induced rats. A high concentration of Dual-Oligo tended to produce more acetic acid than that observed for the control group, and Dual-Oligo affected the production of total SCFA. Bifidobacteria concentration of cecal contents in the high-concentration oligosaccharide (HDO) and low-concentration oligosaccharide (LDO) groups was similar to the result of the normal group. CONCLUSIONS:These results showed that Dual-Oligo is a functional material that is derived from a natural food product and is effective in ameliorating constipation. 10.4162/nrp.2016.10.6.583
    Non-isoflavones Diet Incurred Metabolic Modifications Induced by Constipation in Rats via Targeting Gut Microbiota. Liu Jialin,Chang Ruirui,Zhang Xiaobei,Wang Zhongzhao,Wen Jun,Zhou Tingting Frontiers in microbiology Isoflavones, presenting in leguminous plants and the normal chow diet, are known to alter intestinal microbiota, yet their deficiency has not been widely studied for its effect on constipation in biochemical state of rats. Our previous study discovered the differences in pharmacokinetic traits of isoflavones from Semen fed with normal chow diet (ISO) and non-isoflavones diet (NISO). To gain insight into the key role of intestinal microbiota in constipation and metabolic differences caused by isoflavones deficiency, we observed a significant decrease in fecal pellet numbers, fecal water content, intestinal transit rate together with the serum concentrations of substance P (SP) and vasoactive intestinal peptide (VIP) in NISO group, compared with those in the ISO group. Following 16S rRNA compositional sequencing, results excluded the changes in intestinal microbiota over time and highlighted that a total of 5 phyla and 21 genera changed significantly, among which Firmicutes, Bacteroidetes, Blautia, Prevotella, Lactobacillus and Bifidobacterium were closely related to constipation. In addition, Lactobacillus, produceing β-glucosidase which contribute to biotransform glycosides into aglycons and exert the bioactivities consequently, was decreased after non-isoflavones diet intake. Meanwhile, predicted metagenomics indicated that the pathway of glycan biosynthesis and metabolism was markedly down-regulated after non-isoflavones diet intake. Taken together, the findings suggested that the changes in the dietary components could alter the biochemical state of rats, which may be triggered by the abnormal modifications facilitated by β-glucosidase-producing bacteria. Our study shed a new strategy to explore the relationship among disease phenotypes (D), intestinal microbiota (I), enzymes (E) and traits of metabolism (T) named as "DIET," which can provide a reference for further study of the mechanism in regulation of intestinal bacteria-mediated diet on diseases. 10.3389/fmicb.2018.03002
    Metabolomics approach to serum biomarker for laxative effects of red in loperamide-induced constipation of SD rats. Kim Ji Eun,Lee Young Ju,Ryu Sung Ha,Park Ji Won,Kang Mi Ju,Choi Hyeon Jun,Bae Su Ji,Choi Yusang,Kang Hyun Gu,Kim Kyu-Bong,Kim Suhkmann,Lim Yong,Hwang Dae Youn Laboratory animal research Red (RLP) is a known herbal medicine used in the treatment of some chronic diseases including constipation, neurodegenerative disorders, diabetes and obesity. To determine and characterize putative biomarkers that predict the laxative effects induced by RLP treatment, alteration of endogenous metabolites was measured in the serum of loperamide (Lop)-induced constipation rats after administration of RLP extract (EtRLP) using H nuclear magnetic resonance (H NMR) spectral data. The urine volume and amounts, and weights and water contents of stools were significantly recovered in the Lop + EtRLP treated group as compared to the No group, whereas body weight and food intake maintained constant levels. Also, significant recoveries in the thickness of mucosa and muscle were detected in the colon of the Lop + EtRLP treated group. Furthermore, pattern recognition showed absolutely different clustering of the serum analysis parameters when comparing the Lop treated group and Lop + EtRLP treated group. Of the 33 endogenous metabolites, 7 amino acids (alanine, arginine, glutamate, glutamine, glycine, threonine and valine) and 8 endogenous metabolites (betaine, creatine, glucose, taurine, ethanol, lactate, glycerol and succinate) were dramatically increased in the Lop + EtRLP treated SD rats. These results provide the first evidence pertaining to metabolic changes in the constipation rats treated with Lop + EtRLP. Additionally, these findings correlate with changes observed in 15 metabolites during the laxative effects of EtRLP. 10.1186/s42826-019-0009-x
    Toxicological implications and laxative potential of ethanol root extract of Morella serrata in loperamide-induced constipated Wistar rats. Sabiu Saheed,Ashafa Omotayo Tom Anofi Pharmaceutical biology CONTEXT:Morella serrata L. (Myricaceae) is commonly used in South Africa to treat several diseases including constipation. OBJECTIVES:This study investigated toxicological implications and laxative potential of the ethanol root extract of the plant. MATERIALS AND METHODS:While normal control animals were placed on sterile placebo, the loperamide-constipated rats were treated with the extract at 75, 150 and 300 mg/kg doses for 7 days, and their feeding patterns and faecal properties were monitored. Gastrointestinal transit ratio and the toxicity profile of the tested doses were thereafter evaluated. RESULTS:The significantly increased faecal volume (192.08%), feed (63.63%), water intake (55.97%) and improved intestinal motility (95.05%) in the constipated rats following treatment with the extract (at 300 mg/kg) suggested laxative potential of the extract. The 1.5-2.0-fold normalization of the platelets, erythrocytes and leukocytes counts in the extract-treated constipated rats suggests its non-haematotoxic tendency. Furthermore, the extract (at the highest investigated dose) reversed the attenuation in the concentrations of the electrolytes (0.5-2-fold), total protein (62.12%) and albumin (55.88%) in the constipated animals as well as attenuated activities of hepatic enzymes (0.5-3.0-fold) and levels of urea (126.67%), creatinine (40.32%), cholesterol (3-fold) and triglycerides (9-fold). These further support its non-toxic and therapeutic attributes against constipation. CONCLUSION:Overall, the effect exhibited by M. serrata in this study competed well with Senokot (standard drug) and proved that it may be relatively safe and with excellent laxative potential, thus, supporting its pharmacological applications in South Africa. 10.1080/13880209.2016.1193885
    Complex-oligosaccharide composed of galacto-oligosaccharide and lactulose ameliorates loperamide-induced constipation in rats. Kwon Jung Il,Park Yooheon,Noh Dong Ouk,Suh Hyung Joo,Han Sung Hee Food science and biotechnology The purpose of this study was to compare the beneficial effects of galactooligosaccharide (GOS), lactulose, and a complex-oligosaccharide composed with GOS and lactulose (Com-oligo) on loperamide-induced constipation in SD rats. Rats were randomly divided into the following eight groups: the normal group (Nor); constipation control group (Con); and 6 constipation groups fed low and high doses of GOS, lactulose (Lac), and Com-oligo, respectively. Com-oligo increased intestinal transit ratio and relieved constipation in loperamide-treated rats. The group receiving a high dose of Com-oligo favorably regulated gastrointestinal functions such as pellet number, weight, moisture content, short chain fatty acid, intestinal transit ratio, and bifidobacterium number in constipated rats. In addition, Com-oligo restored peristalsis of the small intestine, morphology of colon, and increased interstitial cells of Cajal area. Thus, providing Com-oligo as an oligosaccharide ingredient in nutritional formulas could benefit the health of the gastrointestinal tract. 10.1007/s10068-017-0300-2
    Laxative effect and mechanism of Tiantian Capsule on loperamide-induced constipation in rats. Li Tian,Hu Mengmeng,Jiang Cuihua,Zhang Dongjian,Gao Meng,Xia Jianwei,Miao Mengqi,Shi Gaofeng,Li Hui,Zhang Jian,Yin Zhiqi Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:Tiantian capsule (TTC), as a functional food, which consists of four herb medicines, including Aloe vera Burm.f. (25%), leaf juices, dried; Cucurbita moschata Duch. (25%), fructus, dried; Poria cocos (Schw.) Wolf. (12.5%), sclerotium, dried; Tremella fuciformis Berk. (12.5%), fruiting bodies, dried, and one extract xylooligosaccharides (25%) from Maize Cob by enzymolysis, has been commonly used in China to ameliorate constipation. AIM OF THE STUDY:The aim of the work is to elucidate the potential laxative mechanisms of TTC in loperamide-induced constipated rats. MATERIALS AND METHODS:LC-MS/MS was employed for analyzing the TTC extract. The gastrointestinal transit was evaluated by X-ray. The H&E and Alcian-Blue stain were applied to determine the changes of goblet cells and mucus layer, respectively. Meanwhile, levels of neurotransmitters were evaluated by enzyme-linked immunosorbent assay. The protein expressions were also measured by immunohistochemistry and Western blot. RESULTS:Our results showed that TTC administration attenuated constipation responses in aspects of fecal pellets number, water content of feces, stomach emptying and gastrointestinal transit. Further investigations revealed that TTC treatment not only induced the recovery of neurotransmitters, such as motilin, substance P, somatostatin, endothelin and vasoactive intestinal peptide, but also up-regulated the expressions of c-kit and stem cell factor (SCF). Additionally, the number of goblet cells and thickness of the mucus layer were elevated, and the guanylate cyclase C-cGMP signal pathway was also up-regulated after TTC treatment. CONCLUSION:Our findings demonstrated that the laxative effect of TTC in constipation rats is probably due to the regulation of bowel movement and intestinal fluid secretion. 10.1016/j.jep.2020.113411
    Buzhongyiqi Decoction Protects Against Loperamide-Induced Constipation by Regulating the Arachidonic Acid Pathway in Rats. Ju Wan-Jun,Zhao Ze-Kuo,Chen Shao-Li,Zhou Dan-Dan,Yang Wen-Ning,Wen Xiao-Ping,Du Guang-Li Frontiers in pharmacology Constipation is a common gastrointestinal disorder without effective treatment approach. Buzhongyiqi decoction (BZYQD) is a classical formula that has been commonly used for gastrointestinal disorders for nearly 1,000 years. In this study, we aimed to investigate the protective effect of BZYQD against loperamide-induced constipation and its potential mechanism. Rats with loperamide-induced constipation were orally administered BZYQD. BZYQD treatment obviously increased the small intestinal transit rate and alleviated colon tissue pathological damage. Subsequently, serum metabolomics study was performed to identify the metabolites affected by BZYQD. Metabolomics identified that the levels of 17 serum metabolites, including prostaglandin E (PGE), arachidonic acid (AA), and inositol, were significantly changed in BZYQD-treated group compared with those in the loperamide-induced group. Pathway analysis revealed that those metabolites were mainly associated with arachidonic acid metabolism, biosynthesis of unsaturated fatty acids, ascorbate and aldarate metabolism, inositol phosphate metabolism. Additionally, BZYQD treatment down-regulated the cyclooxygenase-2 expression and decrease production of the proinflammatory mediator PGE. Further study revealed that BZYQD administration decreased serum levels of the inflammatory factors IL-1β and TNF-α, inhibited phosphorylation of the nuclear transcription factor NF-κB, and down-regulated expression of the inflammatory factors IL-1β and IL-6 in the constipated rat colon. Moreover, BZYQD treatment also increased serum levels of inositol, motilin and gastrin, and promoted gastrointestinal motility. In conclusion, the present study suggested that BZYQD exerted a protective effect against loperamide-induced constipation, which may be associated with its role in regulation of multiple metabolic pathways. 10.3389/fphar.2020.00423
    Prophylactic use of probiotic chocolate modulates intestinal physiological functions in constipated rats. Lee Chul Sang,Tan Pei Lei,Eor Ju Young,Choi Da Hye,Park Miri,Seo Sung Keum,Yoon Seokmin,Yang Siyoung,Kim Sae Hun Journal of the science of food and agriculture BACKGROUND:This study investigated the in vivo prophylactic effect of probiotic chocolate on constipation. Rats were administered chocolate containing 2.5 × 10  CFU g of probiotics daily for 4 weeks and treated with loperamide (5 mg kg ) daily at the fourth week of treatment. RESULTS:Probiotic chocolate treatment significantly (P < 0.05) increased the intestinal motility, colon length, fecal moisture content and number of excreted fecal pellets in constipated rats. Moreover, quantitative real-time polymerase chain reaction data and histological images also revealed that both probiotic chocolate LYC and BB12 treatments were capable of upregulating the mRNA expression levels of colonic ZO-1, occludin and AQP8, leading to the maintenance of the defensive barrier function in the constipated rats compared with the negative controls. Interestingly, these treatments also modulated gut bacterial populations by increasing the abundance levels of Lactobacillus and Bifidobacterium, as well as reducing the abundance level of Enterobacteriaceae. CONCLUSION:The present study demonstrated that probiotic chocolate LYC and BB12 could potentially be used as alternative agents for prophylactic constipation. © 2018 Society of Chemical Industry. 10.1002/jsfa.9518
    Effects of Hemp seed soft capsule on colonic ion transport in rats. Lu Xiao-Fang,Jia Meng-Di,Zhang Sheng-Sheng,Zhao Lu-Qing World journal of gastroenterology AIM:To investigate the effect of Hemp seed soft capsule (HSCC) on colonic ion transport and its related mechanisms in constipation rats. METHODS:Sprague-Dawley male rats were randomly divided into three groups: normal group, constipation group and HSSC group. Rats in the constipation and HSSC groups were administrated loperamide 3 mg/kg per day orally for 12 d to induce the constipation model. Then, the HSSC group was given HSSC 0.126 g/kg per day by gavage for 7 d. The normal and constipation groups were treated with distilled water. After the treatment, the fecal wet weight and water content were measured. The basal short-circuit current () and resistance were measured by an Ussing Chamber. Besides the drug delivery experiment above, an drug application experiment was also conducted. The accumulative concentrations of HSSC (0.1 mg/mL, 0.5 mg/mL, 1.0 mg/mL, 2.5 mg/mL, 5.0 mg/mL, 10.0 mg/mL and 25.0 mg/mL) were added to the normal isolated colonic mucosa and the was recorded. Further, after the application of either ion (Cl or HCO) substitution, ion channel-related inhibitor (N-phenylanthranilic acid, glybenclamide, 4,4-diisothiocyano-2,2-stilbenedisulfonic acid or bumetanide) or neural pathway inhibitor [tetrodotoxin (TTX), atropine, or hexamethonium], the induced by HSSC was also measured. RESULTS:In the constipation group, the fecal wet weight and the water content were decreased in comparison with the normal group ( < 0.01). After the treatment with HSSC, the fecal wet weight and the water content in the HSSC group were increased, compared with the constipation group ( < 0.01). In the constipation group, the basal was decreased and resistance was increased, in comparison with the normal group ( < 0.01). After the treatment with HSSC, the basal was increased ( < 0.05) and resistance was decreased ( < 0.01) in the HSSC group compared with the constipation group. In the experiment, beginning with the concentration of 1.0 mg/mL, differences in were found between the experimental mucosa (with HSSC added) and control mucosa. The of experimental mucosa was higher than that of control mucosa under the same concentration (1.0 mg/mL, < 0.05; 2.5-25 mg/mL, < 0.01). After the Cl or HCO removal and pretreated with different inhibitors (cAMP-dependent and Ca-dependent Cl channels, Na-K-2Cl cotransporter (NKCC), Na-HCO cotransporter or Cl/HCO exchanger inhibitor), there were differences between experimental mucosa and control mucosa; the of experimental mucosa was lower than that of control mucosa under the same concentration ( < 0.05). Meanwhile, after pretreatment with neural pathway inhibitor (TTX, atropine, or hexamethonium), there were no differences between experimental mucosa and control mucosa under the same concentration ( > 0.05). CONCLUSION:HSSC ameliorates constipation by increasing colonic secretion, which is mediated the coaction of cAMP-dependent and Ca-dependent Cl channels, NKCC, Na-HCO cotransporter or Cl/HCO exchanger. 10.3748/wjg.v23.i42.7563
    The effect of Aloe ferox Mill. in the treatment of loperamide-induced constipation in Wistar rats. Wintola Olubunmi A,Sunmonu Taofik O,Afolayan Anthony J BMC gastroenterology BACKGROUND:Constipation is the most common gastrointestinal complaint all over the world and it is a risk factor of colorectal cancer. In this study, the efficacy of aqueous leaf extract of Aloe ferox Mill. was studied against loperamide-induced constipation in Wistar rats. METHODS:Constipation was induced by oral administration of loperamide (3 mg/kg body weight) while the control rats received normal saline. The constipated rats were treated with 50, 100 and 200 mg/kg body weight/day of the extract for 7 days during which the feeding characteristics, body weight, fecal properties and gastrointestinal transit ratio were monitored. RESULTS:The extract improved intestinal motility, increased fecal volume and normalized body weight in the constipated rats, which are indications of laxative property of the herb with the 200 mg/kg body weight of the extract showing the best efficacy. CONCLUSION:The effect of the extract compares favourably well with senokot, a standard laxative drug. These findings have therefore, lent scientific credence to the folkloric use of the herb as a laxative agent by the people of the Eastern Cape of South Africa. 10.1186/1471-230X-10-95
    Physicochemical properties and laxative effects of polysaccharides from Anemarrhena asphodeloides Bge. in loperamide-induced rats. Li Xiaomao,Liu Yan,Guan Wei,Xia Yonggang,Zhou Yuanyuan,Yang Bingyou,Kuang Haixue Journal of ethnopharmacology ETHNOPHARMACOLOGICAL RELEVANCE:As a traditional Chinese herbal medicine, Anemarrhena asphodeloides Bge. possesses the effects of nourishing yin, moistening dryness, clearing lungs and relieving fire. Simultaneously, it has been used to treat constipation for more than one thousand years in China. However, modern medical studies are limited and lacking on its therapeutic mechanism. AIM OF THE STUDY:This current study was aimed to investigate the laxative activities and explore the potential mechanism of Anemarrhena asphodeloides Bge. polysaccharides (AABP) in loperamide-induced constipation rats. MATERIALS AND METHODS:The structure of AABP was determined by using infrared spectrum, high performance gel permeation chromatography (HPGPC), and high performance liquid chromatography (HPLC). Real-time quantitative polymerase chain reaction (PCR), multitudinous methods were adopted to explore the underlining therapeutic mechanism of AABP in treating constipation, including enzyme-linked immunosorbent assay (ELISA), histopathological, immunohistochemistry and western blotting. RESULTS:In the present study, the average molecular weight of AABP was determined as 1.11 × 10 kDa. The primary monosaccharide compositions were analyzed including D-mannose, L-rhamnose, D-galacturonic acid, D-glucose, D-galactose and L-arabinose (1, 0.04, 0.53, 0.11, 0.33, 0.25, respectively) by high-performance liquid chromatography (HPLC). AABP significantly increased the levels of gastrin (Gas), motilin (MTL), substance P (SP), 5-hydroxytryptamine (5-HT) and vasoactive intestinal peptide (VIP), and decreased the NO content of loperamide-induced rats to ameliorate constipation in the rats. Whilst, AABP repaired the damaged colons by regulating PCNA and ICAM-1 protein expressions. Additionally, AABP up-regulated the levels of SCF, c-Kit, AQP3 and VIP as well as down-regulated the expressions of AQP8, AQP4 and PGE2. CONCLUSION:The present findings suggested that AABP were the laxative active ingredients isolated from Anemarrhena asphodeloides Bge., which could treat constipation through regulating the gastrointestinal hormones and neurotransmitters to improve the intestinal motility and water metabolism. 10.1016/j.jep.2019.111961
    [Effects of zhizhu tongbian decoction on the colon ink propelling rate, GDNF, and NOS mRNA expression in rats with slow transit constipation]. Fan Yi-Hong,Xu Guo-Ping,Feng Wen Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine OBJECTIVE:To observe the effects of Zhizhu Tongbian Decoction (ZTD) on the enteric nervous system, mRNA expressions of glial cell line derived neurotrophic factor (GDNF) and nitric oxide synthase (NOS) in the slow transit constipation (STC) rats. METHODS:Thirty STC rat model was established by gastric irrigation of rhubarb. After the model building, they were randomly divided into three groups, i. e., the model group, the high dose ZTD group, and the low dose ZTD group, 10 in each. Another 10 rats were selected as the blank control group. Rats in the high dose ZTD group and the low dose ZTD group were administered with ZTD (at the daily dose of crude drug 4.8 g/kg and 2.4 g/kg respectively) by gastrogavage. Normal saline was given to rats in the blank control group and the model group. The ink propelling rate was determined using ink propelling test. Meantime, mRNA expressions of GDNF and NOS in the rat colon were measured using reverse transcriptional polymerase chain reaction (RT-PCR). RESULTS:Compared with the blank control group, the ink propelling rate and GDNF mRNA expression decreased, and NOS mRNA increased in the model group, showing statistical difference (P<0.01, P<0.05). Compared with the model group, the ink propelling rate increased in the high and low dose ZTD groups (P<0.01, P<0.05). The mRNA expressions of GDNF increased and the mRNA expressions of NOS decreased in the high dose ZTD group with statistical difference (P<0.01, P<0.05). But there was no difference in any index between the high and low dose ZTD groups. CONCLUSION:High dose ZTD could obviously improve the intestinal transmission function possibly through up-regulating the mRNA expressions of GDNF and down-regulating the mRNA expressions of NOS in STC rats.
    7,8-Dihydroxyflavone Enhanced Colonic Cholinergic Contraction and Relieved Loperamide-Induced Constipation in Rats. Ma Li,Qu Zhiqiang,Xu Luo,Han Lei,Han Qingfang,He Juan,Luan Xiao,Wang Bingxiang,Sun Yongye,He Baoguo Digestive diseases and sciences BACKGROUND:Whether 7,8-dihydroxyflavone (7,8-DHF), a tyrosine kinase receptor B (TrkB) agonist, modulates colonic smooth muscle motility and/or alleviates constipation has not yet been studied. AIMS:Here, we aimed to determine how 7,8-DHF influences carbachol (CCh)-stimulated contraction of colonic strips and the in vivo effect of 7,8-DHF on constipation. METHODS:Muscle strips were isolated from rat colons for recording contractile tension and performing western blotting. Constipation was induced in rats with loperamide. RESULTS:Although it specifically activated TrkB, 7,8-DHF applied alone neither activated PLCγ1 in the colonic strips nor induced colonic strip contraction. However, 7,8-DHF enhanced CCh-stimulated PLCγ1 activation and strip contraction. The PLCγ1 antagonist U73122 suppressed both CCh-stimulated and 7,8-DHF-enhanced/CCh-stimulated contraction. While clarifying the underlying mechanism, we revealed that 7,8-DHF augmented muscarinic M3 receptor expression in the colonic strips. The M3-selective antagonist tarafenacin specifically inhibited the 7,8-DHF-enhanced/CCh-stimulated contraction of the colonic strips. Since 7,8-DHF increased Akt phosphorylation, and LY294002 (an antagonist of PI3K upstream of Akt) dramatically inhibited both 7,8-DHF-augmented M3 expression and 7,8-DHF-enhanced/CCh-stimulated contractions, we assumed that 7,8-DHF/TrkB/Akt was associated with the modulation of M3 expression in the colonic strips. ANA-12, a specific TrkB antagonist, not only inhibited TrkB activation by 7,8-DHF but also suppressed 7,8-DHF-enhanced cholinergic contraction, 7,8-DHF/CCh-mediated activation of PLCγ1/Akt, and M3 overexpression in colonic strips. In vivo 7,8-DHF, also by promoting intestinal motility and M3 expression, significantly alleviated loperamide-induced functional constipation in rats. CONCLUSIONS:Our results suggest that 7,8-DHF regulates colonic motility possibly via a TrkB/Akt/M3 pathway and may be applicable for alleviating constipation. 10.1007/s10620-020-06817-y
    Effect of colic vein ligature in rats with loperamide-induced constipation. Neri Flavia,Cavallari Giuseppe,Tsivian Matvey,Bianchi Elisa,Aldini Rita,Cevenini Monica,Guidetti Elena,Piras Gian Luca,Pariali Milena,Nardo Bruno Journal of biomedicine & biotechnology INTRODUCTION:Medical treatment in chronic constipation is not always successful. Surgery is indicated in unresponsive selected severe cases. This study presents the distal venous colic ligation in rat as a novel surgical approach. MATERIALS AND METHODS:16 rats (study group) were evaluated in 3 phases of 6 days each: A (normal conditions), B (loperamide-induced constipation), and C (colic vein legation) and compared with rats treated in phase C with PEG 4,000 (control group). Blood biochemical and physiological parameters, daily fecal water content (FWC), and histological analysis were performed in all study phases. RESULTS:No biochemical and physiological parameters changes were observed. FWC decreased in phase B and increased in phase C in both groups with a grow up to 2.3-fold in study group compared to control (P < 0.0001). Moreover, in study group, a high number of colonic goblet cells were detected (phase C versus phase B: P < 0.001) while no differences were registered in control. CONCLUSION:By ligature of the colic vein in constipated rats, an increase in FWC and goblet cells higher than in PEG treated rats was detected. The described surgical procedure appeared effective, simple, and safe; further studies in animal models, however, are necessary to assess its clinical applicability. 10.1155/2012/896162
    Amylase-Producing Maltooligosaccharide Provides Potential Relief in Rats with Loperamide-Induced Constipation. Jang Eun Yeong,Ahn Yejin,Suh Hyung Joo,Hong Ki-Bae,Jo Kyungae Evidence-based complementary and alternative medicine : eCAM Constipation is a chronic disease caused by infrequent, inadequate, and difficult bowel movements. The present study aimed to evaluate the potential laxative effect of maltooligosaccharide (MOS) on loperamide-induced constipation in a rat model. experiments were conducted to evaluate the effect of MOS on the growth of lactic acid bacteria. Moreover, to examine the effect of MOS administration on Sprague-Dawley (SD) rats with loperamide-induced constipation, the drinking water for the rats was supplemented with 10% or 15% of MOS for 14 days, and, thereafter, the improvement in constipation was assessed. For this, the rats were divided into five groups: normal (Nor), loperamide-induced constipated (Con), positive control (15% of dual-oligosaccharide (DuO-15)), 10% MOS treated (MOS-10), and 15% MOS-treated (MOS-15). In an test, MOS treatment promoted the growth of lactic acid bacteria except . Treatment with higher MOS dose relieved constipation in rats by improving the fecal pellet and water content. Furthermore, in the high MOS dose group, the cecal short-chain fatty acid levels significantly increased compared to those in the control group ( < 0.001). MOS treatment also improved the mucosal thickness as well as mucin secretion and increased the area of intestinal Cajal cells compared to that in the control group ( < 0.001). These findings suggest that MOS relieves constipation and has beneficial effect on the gastrointestinal tract, and, therefore, it can be used as an ingredient in functional foods for treating constipation or improving intestinal health. 10.1155/2020/5470268
    The use of Euphorbia hirta L. (Euphorbiaceae) in diarrhea and constipation involves calcium antagonism and cholinergic mechanisms. Ali Muhammad Zeeshan,Mehmood Malik Hassan,Saleem Muhammad,Gilani Anwarul-Hassan BMC complementary medicine and therapies BACKGROUND:Euphorbia hirta (Linn) family Euphorbiaceae has been used in indigenous system of medicine for the treatment of gastrointestinal disorders. This study was designed to determine the pharmacological basis for the medicinal use of E. hirta in diarrhea and constipation. METHODS:The aqueous-methanol extract of whole herb of E. hirta (EH.Cr) and its petroleum ether (Pet.EH), chloroform (CHCl.EH), ethyl acetate (Et.Ac.EH) and aqueous (Aq.EH) fractions were tested in the in-vivo experiments using Balb/c mice, while the in-vitro studies were performed on isolated jejunum and ileum preparations of locally bred rabbit and Sprague Dawley rats, respectively, using PowerLab data system. RESULTS:Qualitative phytochemical analysis showed the presence of alkaloids, saponins, flavonoids, tannins, phenols, cardiac glycosides, while HPLC of EH.Cr showed quercetin in high proportion. In mice, EH.Cr at the dose of 500 and 1000 mg/kg showed 41 and 70% protection from castor oil-induced diarrhea, respectively, similar to the effect of quercetin and loperamide, while at lower doses (50 and 100 mg/kg), it caused an increase in the fecal output. In loperamide-induced constipated mice, EH.Cr also displayed laxative effect with respective values of 28.6 and 35.3% at 50 and 100 mg/kg. In rabbit jejunum, EH.Cr showed atropine-sensitive inhibitory effect in a concentration-dependent manner, while quercetin and nifedipine exhibited atropine-insensitive effects. Fractions of E. hirta also produced atropine-sensitive inhibitory effects except Pet.EH and CHCl.EH. On high (80 mM) and low (20 mM) K - induced contractions, the crude extract and fractions exhibited a concentration-dependent non-specific inhibition of both spasmogens and displaced concentration-response curves of Ca to the right with suppression of the maximum effect similar to the effect quercetin and nifedipine. Fractions showed wide distribution of spasmolytic and Ca antagonist like effects. In rat ileum, EH.Cr and its fractions exhibited atropine-sensitive gut stimulant effects except Pet.EH. CONCLUSION:The crude extract of E. hirta possesses antidiarrheal effect possibly mediated through Ca antagonist like gut inhibitory constituents, while its laxative effect was mediated primarily through muscarinic receptor agonist like gut stimulant constituents. Thus, these findings provide an evidence to the folkloric use of E. hirta in diarrhea and constipation. 10.1186/s12906-019-2793-0
    Effects of Ficus carica paste on loperamide-induced constipation in rats. Lee Hak-Yong,Kim Jung-Hoon,Jeung Han-Wool,Lee Cha-Uk,Kim Do-Sung,Li Bo,Lee Geum-Hwa,Sung Myung-Soon,Ha Ki-Chan,Back Hyang-Im,Kim Sun-Young,Park Soo-Hyun,Oh Mi-Ra,Kim Min-Gul,Jeon Ji-Young,Im Yong-Jin,Hwang Min-Ho,So Byung-Ok,Shin Sook-Jeong,Yoo Wan-Hee,Kim Hyung-Ryong,Chae Han-Jung,Chae Soo-Wan Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association OBJECTIVE:Constipation is one of the most common gastrointestinal complaints worldwide. This study examined the effects of fig (Ficus carica L.) paste for the treatment of loperamide-induced constipation in a rat model. METHODS:Animals were divided into one normal control group and four experimental groups (0, 1, 6, and 30 g/kg). Loperamide (2 mg/kg, twice per day) was injected intraperitoneally to induce constipation in the four experimental groups. Fig paste was administered for 4 weeks to assess its anti-constipation effects. RESULTS:Fecal pellet number, weight and water content were increased in the fig-treated groups as compared to the control group. Reductions in body weight and increased intestinal transit length were observed in the fig-treated groups. Fecal pellet number was reduced in the distal colons of the fig-treated rats. Exercise and ileum tension increased in the experimental groups as compared to the control group. According to histological analyses, the thickness of the distal colon and areas of crypt epithelial cells that produce mucin were increased in the fig-treated groups in a dose-dependent manner. CONCLUSION:Constipation was decreased when fig fruit was fed to rats. Specifically, fecal number, weight, and water content, as well as histological parameters such as thickness and mucin areas in the distal colon were improved. Fig treatment may be a useful therapeutic and preventive strategy for chronic constipation. 10.1016/j.fct.2011.12.001
    Aqueous extracts of Liriope platyphylla induced significant laxative effects on loperamide-induced constipation of SD rats. Kim Ji Eun,Lee Young Ju,Kwak Moon Hwa,Ko Jun,Hong Jin Tae,Hwang Dae Youn BMC complementary and alternative medicine BACKGROUND:Liriope platyphylla has long been reported as a therapeutic drug for treatment of various human chronic diseases including inflammation, diabetes, neurodegenerative disorders, obesity, and atopic dermatitis. To investigate the laxative effects of L. platyphylla, alterations in excretion parameters, histological structure, mucin secretion, and related protein levels were investigated in rats with loperamide (Lop)-induced constipation after treatment with aqueous extract of L. platyphylla (AEtLP). METHODS:Alterations on constipation phenotypes were measured in rats with Lop-induced constipation after treatment with AEtLP using excretion parameter analysis, histological analysis, RT-PCR, western blot and transmission electron microscope (TEM) analysis. RESULTS:The amounts of stool and urine excretion were significantly higher in the Lop + AEtLP-treated group than in the Lop + vehicle-treated group, whereas food intake and water consumption were maintained at constant levels. AEtLP treatment also induced an increase in villus length, crypt layer, and muscle thickness in the constipation model. Total mucin secretion was higher in the Lop + AEtLP-treated group than in the Lop + vehicle-treated group, although mucin secretion per crypt was very similar among all groups. Furthermore, RT-PCR and western blot revealed a dramatic reduction of key factors level on the muscarinic acetylcholine receptors (mAChRs) signaling pathway in the Lop + AEtLP-treated group relative to the Lop + vehicle-treated group. Especially, the accumulation of lipid droplets in enterocytes of crypts following Lop treatment was improved to the level of the No-treated group in response to AEtLP treatment. CONCLUSION:These results suggest that AEtLP improves constipation induced by Lop treatment through an increase in crypt layer and stimulation of lipid droplet secretions. These data are the first to show that the laxative effects of AEtLP are closely related to the down-regulation of mAchRs and their downstream signals. 10.1186/1472-6882-13-333
    The effect and mechanism of electroacupuncture at LI11 and ST37 on constipation in a rat model. Zhu Xianwei,Liu Zhibin,Qu Hongyan,Niu Wenmin,Gao Li,Wang Yuan,Zhang Aimin,Bai Lu Acupuncture in medicine : journal of the British Medical Acupuncture Society BACKGROUND:Electroacupuncture (EA) is used clinically for the treatment of constipation. Serotonin (5-hydroxytryptamine, 5-HT) plays an important role in colonic motility; however it is unknown whether alterations in colonic 5-HT are associated with EA. In this study, the effect and mechanism of EA at acupuncture points LI11 and ST37 were examined using a cold saline-induced rat model of constipation. METHODS:A rat constipation model was induced by cold saline gavage in 24 Sprague-Dawley rats. A further six rats were included as a Control group. The constipated rats were divided into four groups (n=6 each): a Constipation group that remained untreated; a Constipation+LI11 group that received EA at LI11; a Constipation+ST37 groups that received EA at ST37; and a Constipation+LI11+ST37 group that received EA at both LI11 and ST37. After EA treatment, faecal water content, defaecation frequency, and gastrointestinal (GI) transit were measured, as well as the expression of tryptophan hydroxylase (TPH) in colonic tissues (by Western blot analysis) and 5-HT in both faeces and colonic tissues (by ELISA). RESULTS:All three EA-treated groups demonstrated significant improvements in faecal water content, defaecation frequency and GI transit (p<0.05). In addition, TPH and 5-HT expression were both increased by EA at LI11 and/or ST37 (p<0.05). There were no significant differences between the three EA groups for any outcomes. CONCLUSIONS:EA at LI11 and/or ST37 had a positive effect on objective markers of constipation in a rat model. In addition, EA increased 5-HT and TPH in the colonic tissues. 10.1136/acupmed-2015-010897
    Total Glucosides of Paeony Promote Intestinal Motility in Slow Transit Constipation Rats through Amelioration of Interstitial Cells of Cajal. Zhu Feiye,Xu Shan,Zhang Yongsheng,Chen Fangming,Ji Jinjun,Xie Guanqun PloS one OBJECTIVES:Using an atropine-diphenoxylate-induced slow transit constipation (STC) model, this study explored the effects of the total glucosides of paeony (TGP) in the treatment of STC and the possible mechanisms. STUDY DESIGN:A prospective experimental animal study. METHODS:The constipation model was set up in rats with an oral gavage of atropine-diphenoxylate and then treated with the TGP. The volume and moisture content of the faeces were observed and the intestinal kinetic power was evaluated. Meanwhile, the colorimetric method and enzyme linked immunosorbent assay (ELISA) were employed to determine the changes of nitric oxide (NO), nitric oxide synthase (NOS), vasoative intestinal peptide (VIP) and the P substance (SP) in the serum, respectively. The protein expressions of c-kit and stem cell factor (SCF) were assessed by immunohistochemical analysis and western blot, respectively, and the mRNA level of c-kit was measured by a reverse transcription polymerase chain reaction (RT-PCR). RESULTS:The TGP attenuated STC responses in terms of an increase in the fecal volume and moisture content, an enhancement of intestinal transit rate and the reduction of NO, NOS and VIP in the serum. In addition, the c-kit, a labeling of interstitial cells of Cajal (ICC) increased at both protein and mRNA levels. SCF, which serves as a ligand of c-kit also increased at protein level. CONCLUSION:The analysis of our data indicated that the TGP could obviously attenuate STC through improving the function of ICC and blocking the inhibitory neurotransmitters such as NO, NOS and VIP. 10.1371/journal.pone.0160398
    Gallotannin-Enriched Extract Isolated from Galla Rhois May Be a Functional Candidate with Laxative Effects for Treatment of Loperamide-Induced Constipation of SD Rats. Kim Ji Eun,Go Jun,Koh Eun Kyoung,Song Sung Hwa,Sung Ji Eun,Lee Hyun Ah,Lee Young Hee,Hong Jin Tae,Hwang Dae Youn PloS one Several natural products containing tannins are used as traditional medicines for treatment of constipation; however, their pharmacological mechanism is not well understood. The laxative effects of gallotannin-enriched extract isolated from Galla Rhois (GEGR) were investigated using a constipation model induced by loperamide (Lop) injection. After analysis for antioxidant activity of GEGR, alterations in the excretion parameters, histological structure, mucin secretion, and related protein levels were measured in the transverse colon of Sprague Dawley (SD) rats with Lop-induced constipation following treatment with 250, 500 and 1,000 mg/ml of GEGR. The number and weight of feces increased significantly by 48-79% and 128-159%, respectively, in the Lop+GEGR treated group relative to the Lop+vehicle treated group, while food intake and water consumption were maintained at a constant level. The thickness of mucosa, muscle and flat luminal surface, as well as the number of goblet cells and crypt of lieberkuhn were enhanced in the Lop+GEGR treated group. Moreover, mucin secretion increased significantly in a dose dependent manner in the Lop+GEGR treated group. Furthermore, the downstream signaling pathway of the muscarinic acetylcholine receptors (mAChR) M2 and M3 was recovered by GEGR treatment, although the expression level varied. The levels of Gα expression and inositol triphosphate (IP3) concentration were also recovered in the Lop+GEGR treated group relative to the Lop+vehicle treated group. The results of the present study provide strong evidence that tannins distributed in various medicinal plants are important candidates for improving chronic constipation induced by Lop treatment in animal models. 10.1371/journal.pone.0161144
    Characterization of Changes in Global Genes Expression in the Distal Colon of Loperamide-Induced Constipation SD Rats in Response to the Laxative Effects of Liriope platyphylla. Kim Ji Eun,Park So Hae,Kwak Moon Hwa,Go Jun,Koh Eun Kyoung,Song Sung Hwa,Sung Ji Eun,Lee Hee Seob,Hong Jin Tae,Hwang Dae Youn PloS one To characterize the changes in global gene expression in the distal colon of constipated SD rats in response to the laxative effects of aqueous extracts of Liriope platyphylla (AEtLP), including isoflavone, saponin, oligosaccharide, succinic acid and hydroxyproline, the total RNA extracted from the distal colon of AEtLP-treated constipation rats was hybridized to oligonucleotide microarrays. The AEtLP treated rats showed an increase in the number of stools, mucosa thickness, flat luminal surface thickness, mucin secretion, and crypt number. Overall, compared to the controls, 581 genes were up-regulated and 216 genes were down-regulated by the constipation induced by loperamide in the constipated rats. After the AEtLP treatment, 67 genes were up-regulated and 421 genes were down-regulated. Among the transcripts up-regulated by constipation, 89 were significantly down-regulated and 22 were recovered to the normal levels by the AEtLP treatment. The major genes in the down-regulated categories included Slc9a5, klk10, Fgf15, and Alpi, whereas the major genes in the recovered categories were Cyp2b2, Ace, G6pc, and Setbp1. On the other hand, after the AEtLP treatment, ten of these genes down-regulated by constipation were up-regulated significantly and five were recovered to the normal levels. The major genes in the up-regulated categories included Serpina3n, Lcn2 and Slc5a8, whereas the major genes in the recovered categories were Tmem45a, Rerg and Rgc32. These results indicate that several gene functional groups and individual genes as constipation biomarkers respond to an AEtLP treatment in constipated model rats. 10.1371/journal.pone.0129664
    [Effect of application of herbal medicine paste to "Tianshu" (ST25)on intestinal mobility and expression of vasoactive intestinal peptide and substance P in colonic myenteric plexus in rats with functional constipation]. Meng Xiao-Meng,Liu Xiao-Ting Zhen ci yan jiu = Acupuncture research OBJECTIVE:To observe the effect of acupoint application at bilateral "Tianshu" (ST25) on intestinal mobility and immunoactivity of vasoactive intestinal peptide (VIP) and substance P (SP) in colonic myenteric plexus of rats with functional constipation (FC), so as to analyze its mechanisms underlying improving FC. METHODS:Forty male SD rats were randomly divided into 4 groups, namely normal control, model, acupoint application and medication, with 10 rats in each group. The FC model was established by gavage of Loperamide Hydrochloride suspension fluid (0.5 mg/mL, 3 mg·kg·d) for 7 days. Herbal medicine paste (composed of Rheum Officinale, Sodium Sulfate, Mangnolia Officinalis, etc.) was applied to bilateral ST25 for 6 h, once daily for 4 weeks. Rats of the medication group were treated by gavage of Mosapride suspension fluid (0.15 mg/mL, 1.58 mg·kg·d) for 4 weeks. After the treatment, the rats were deprived of water for 12 hours, and then treated by gavage of 2 mL of activated carbon suspension, followed by recording the first black defecation time and the number of fecal particles and water content of feces within 6 h so as to assess the intestinal mobility. The immunoactivity and average surface density of VIP and SP positive granules in the colonic myenteric plexus were detected by immunohistochemistry. RESULTS:Compared with the normal control group, the first black defecation time was significantly prolonged, and the number and water content of fecal particles within 6 h, and the expression and the average surface density of VIP and SP were significantly reduced in the model group (0.01). After the treatment and compared with the model group, the first black defecation time was shortened, and the fecal water content and fecal particle number within 6 h, as well as the expression and the average surface density of VIP and SP were considerably increased in both acupoint application and medication groups (0.01). There were no significant differences between the acupoint application and medication groups in all the indexes mentioned above after the interventions (0.05). CONCLUSION:Acupoint application may improve the intestinal motility in FC rats, which may be asso-ciated with its effects in up-regulating the immunoactivity of VIP and SP in colonic myenteric plexus of the large intestine. 10.13702/j.1000-0607.180760
    The combination of Cassia obtusifolia L. and Foeniculum vulgare M. exhibits a laxative effect on loperamide-induced constipation of rats. Jang Seung Hee,Yang Dong Kwon PloS one Chronic constipation is a functional gastrointestinal disease that is detrimental to the quality of patient life. Cassia obtusifolia L. (CO) and Foeniculum vulgare M. (FV) are commonly used as medicinal foods in many countries. We aimed to examine the laxative effect and their underlying mechanism of CO and FV mixture on loperamide (lop)-induced constipated rats. To determine the laxative effects of these compounds, Sprague-Dawley rats were divided into six groups: the control, lop-induced constipated (2mg/kg), and three doses (100, 300, and 500mg/kg) of CO and FV mixture-, and Bisacodyl (bis, 3.3mg/kg)-treated groups. The mixture of CO and FV and bis were orally administered once a day for 4 weeks. For induction of constipation, the lop were treated with a dose of 2 mg/kg twice a day on the 3rd week after treatments of CO and FV extracts and bis. The results were revealed that the CO and FV mixture has the laxative effects more than those in CO and FV-alone treatments on constipated rats by determining the stool parameters, including stool number and weight. Indeed, stool parameters, such as, stool number, weight, and water contents and colonic peristalsis from the intestinal transit length and ratio were dramatically improved by CO and FV mixture treatment. Histological study also revealed that CO and FV mixture enhanced the thicknesses of mucosa and muscular layers of the colon in constipated rats. For their underlying mechanism, the mRNAs and proteins expression of muscarinic acetylcholine receptors (mAchR) M2 and M3 and their downstream signaling were preserved by CO and FV mixture treatment in constipated rats. Therefore, this study suggests that treatment with CO and FV mixture has beneficial effects against constipation. We further suggest that CO and FV mixture may be utilized as an alternative therapeutic strategy for constipation. 10.1371/journal.pone.0195624